Prototyping an Ontological Framework for Cellular Senescence Mechanisms: A Homeostasis Imbalance Perspective

Although cellular senescence is a key factor in organismal aging, with both positive and negative effects on individuals, its mechanisms remain largely unknown. Thus, integrating knowledge is essential to explain how cellular senescence manifests in tissue damage and age-related diseases. Here, we propose an ontological model that organizes knowledge of cellular senescence in a computer-readable form. We manually annotated and defined cellular senescence processes, molecules, anatomical structures, phenotypes, and other entities based on the Homeostasis Imbalance Process ontology (HOIP). We described the mechanisms as causal relationships of processes and modelled a homeostatic imbalance between stress and stress response in cellular senescence for a unified framework. HOIP was assessed formally, and the relationships between cellular senescence and diseases were inferred for higher-order knowledge processing. We visualized cellular senescence processes to support knowledge utilization. Our study provides a knowledge base to help elucidate mechanisms linking cellular and organismal aging.

Supplementary Table S2 Common processes in chronic cellular senescence course (HOIP:0060195) and COVID-19 infectious courses: A unified representation of cellular senescence courses.

Supplementary Figure S2
Examples of validation of causal networks including part of the whole ('has part') relations of processes by ontology reasoning tool ELK in Protégé.
In reasoning, direct and indirect causal relationships are inferred using the transitive property (owl: Transitive Property).
Main cellular senescence-related terms defined in the HoIP ontology． HOIP: http://purl.bioontology.org/ontology/HOIPE.g., HOIP:0060195 http://purl.bioontology.org/ontology/HOIP/HOIP_0060195PR: http://purl.obolibrary.org/obo/pr.owlE.g., PR:P42772 http://purl.obolibrary.org/obo/PR_P42772 The upper figure shows a screenshot of OntoGraf in Protégé displaying the imbalance model in the embryonic cellular senescence course, with 'Arc Types' selected to be causal relationships ("has result") for the cellular senescence process.Lower indicates a partial excerpt of the causal relationships (shown in "->") using the 'export DOT' function from OntoGraf.In embryonic cellular senescence, the cellular-stress imbalance could result in cellular senescence (transient).Consequently, tissue remodeling could cause pattern formation specification.(b) (b) The upper figure depicts causal relationships introduced by the imbalance model in the acute cellular senescence course using OntoGraf in Protégé.In the case of acute cellular senescence, there is increasing demand for the oncogenic stress response, which has the subprocess PTEN loss, and the imbalance could lead to cellular senescence (transient), tissue repair, and negative regulation of tumor proliferation.(c) (c) The upper figure shows causal relationships introduced by the imbalance model in the chronic cellular senescence course using OntoGraf in Protégé.In chronic cellular senescence, the imbalance could cause persistent cellular senescence, which might lead to SASP secretion, which could cause chronic inflammation.
(a) By inference, a path from ATM signaling (HOIP:0060610) to p21 signaling (HOIP:0060325) could occur in adult cellular senescence.One of the results inferred that ATM signaling (HOIP:0060110) could result in CHK2 signaling (HOIP:0060145), p53 signaling (HOIP:0060055), regulation of gene expression by p53 (HOIP:0060065), and p21 signaling (HOIP:0060325).(b) Inference of p21 signaling (HOIP:0060548) in embryonic cellular senescence (HOIP:0060267).The result indicated that TGF beta signaling (HOIP:0060269), TGF beta receptor signaling (HOIP:0060270), and SMAD signaling (HOIP:0060290) could lead to the regulation of gene expression by SMAD (HOIP:0060276), which might result in p21 signaling (HOIP:0060548).A screenshot for a list of the results of causal inference of the ontology reasoner ELK in Protégé software, including part of whole relations of processes and p21 signaling (HOIP:0060325) in the adult cellular senescence course used in the ELK reasoner in Protégé.The upper red frame shows the possible cause of p21 signaling [adult cellular senescence] for validating causal networks.Inferred information is shown on a yellow background (lower red frame).The DNA damaging response signaling (HOIP:0060337) is inferred to be a subclass of possible cause of p21 signaling [adult cellular senescence] (d) (d) Representation of the inference results in Leaves (https://leaves.riken.jp/).Each node shows the process, and each edge shows the relationship (orange: has part, blue:/has result) between processes.(e) (e) Validation of causal relation network of DNA damage response signaling (HOIP:0060337) by the ontology reasoning tool ELK in Protégé.The results inferred that DNA damage response signaling (HOIP:0060337) has subprocesses, ATR signaling (HOIP:0060140) (upper figure) or ATM signaling (HOIP:0060110) (lower figure), which could cause CHK1 signaling (HOIP:0060144) (upper figure)/CHK2 signaling (HOIP:0060145) (lower figure).This could then result in p53 signaling (HOIP:0060055), regulation of gene expression by p53 (HOIP:0060065), and p21 signaling (HOIP:0060325).chronic cellular senescence course This study describes the chronic cellular senescence course (HOIP_0060195) as a subclass of the adult cellular senescence course.The processes defined in each cellular senescence course were enumerated using the 'has part' relation.For example, processes such as 'chronic inflammation (HOIP_0060113),' were the components of chronic cellular senescence.The equation is shown as follows: Chronic cellular senescence ⊆ (adult cellular senescence course ∩ has part.accumulation of senescent cell (sustained) [chronic cellular senescence] ∩ has part.aging [chronic cellular senescence] ∩ has part.AKT signaling (sustained) [chronic cellular senescence] ∩ has part.arrest of cell cycle G1/S phase transition (sustained) [chronic cellular senescence] ∩ has part.arrest of nuclear DNA replication (sustained) [chronic cellular senescence] ∩ has part.ATM signaling (sustained) [chronic cellular senescence] ∩ has part.ATR signaling (sustained) [chronic cellular senescence] ∩ has part.autophagy [chronic cellular senescence] ∩ has part.CCL2 signaling [chronic cellular senescence] ∩ has part.cell cycle arrest (sustained) [chronic cellular senescence] ∩ has part.cell hyperproliferation signaling (sustained) [chronic cellular senescence] ∩ has part.cellular response to DNA damage stimulus (sustained) [chronic cellular senescence] ∩ has part.cellular response to stress (sustained) [chronic cellular senescence] ∩ has part.cellular senescence (sustained) [chronic cellular senescence course] ∩ has part.cellular stress-response imbalance [chronic cellular senescence] ∩ has part.cGAS activation [chronic cellular senescence] ∩ has part.cGAS signaling [chronic cellular senescence] ∩ has part.CHK1 signaling (sustained) [chronic cellular senescence] ∩ has part.CHK2 signaling (sustained) [chronic cellular senescence] ∩ has part.chromatin remodeling [chronic cellular senescence] ∩ has part.chronic inflammation [chronic cellular senescence] ∩ has part.CXCL1 signaling [chronic cellular senescence] ∩ has part.CXCL8 signaling [chronic cellular senescence] ∩ has part.cyclin B1-CDK1 complex inactivation (sustained) [chronic cellular senescence] ∩ has part.Cyclin D-CDK4/6 complex inactivation (sustained) [chronic cellular senescence] ∩ has part.cyclin E1-CDK2 complex inactivation (sustained) [chronic cellular senescence] ∩ has part.Decreased expression of LMNB1 [chronic cellular senescence] ∩ has part.decreasing PARP1 level [chronic cellular senescence] ∩ has part.decreasing stem cell [chronic cellular senescence] ∩ has part.DNA damage (sustained) [chronic cellular senescence] ∩ has part.DNA damage checkpoint signaling process [chronic cellular senescence] ∩ has part.DNA damage response siganaling [chronic cellular senescence] ∩ has part.DNA replication checkpoint signaling process [chronic cellular senescence] ∩ has part.fibrosis [chronic cellular senescence] ∩ has part.genomic instability [chronic cellular senescence] ∩ has part.HMGB1 activation [chronic cellular senescence] ∩ has part.hypofunction of DNA repair [chronic cellular senescence] ∩ has part.hypofunction of keeping stem cell niche [chronic cellular senescence] ∩ has part.hypofunction of lysosome [chronic cellular senescence] ∩ has part.hypofunction of telomere maintenance in response to DNA damage [chronic cellular senescence] ∩ has part.IL-1 signaling [chronic cellular senescence] ∩ has part.IL-6 signaling [chronic cellular senescence] ∩ has part.increasing demand for cellular stress response (sustained) [chronic cellular senescence] ∩ has part.increasing demand for oncogenic stress response [chronic cellular senescence] ∩ has part.increasing demand for response to oxidative stress [chronic cellular senescence] ∩ has part.increasing extrachromosomal telomeric repeat DNA [chronic cellular senescence] ∩ has part.increasing number of cell division [chronic cellular senescence] ∩ has part.inflammatory cell infiltration [chronic cellular senescence] ∩ has part.innate immune response [chronic cellular senescence] ∩ has part.interleukin-1 alpha production [chronic cellular senescence] ∩ has part.IRF activation [chronic cellular senescence] ∩ has part.lipofuscin deposition [chronic cellular senescence] ∩ has part.LMNB1degradation in lysosome [chronic cellular senescence] ∩ has part.loss of nuclear lamina [chronic cellular senescence] ∩ has part.loss of telomere maintenance via telomeraseis in somatic cell [chronic cellular senescence] ∩ has part.Mitochondrial DNA damage [chronic cellular senescence] ∩ has part.mitochondrial dysfunction [chronic cellular senescence] ∩ has part.mitochondrial membrane fluidity change [chronic cellular senescence] ∩ has part.MK2 signaling [chronic cellular senescence] ∩ has part.mTOR signaling [chronic cellular senescence] ∩ has part.negative regulation of apoptotic process [chronic cellular senescence] ∩ has part.negative regulation of cell cycle G1/S phase transition [chronic cellular senescence] ∩ has part.negative regulation of cell cycle G2/M phase transition (sustained) [chronic cellular senescence] ∩ has part.negative regulation of double-strand break repair via homologous recombination [chronic cellular senescence] ∩ has part.negative regulation of double-strand break repair via nonhomologous end joining ∩ has part.negative regulation of double-strand break repair via nonhomologous end joining [chronic cellular senescence] ∩ has part.negative regulation of nuclear cell cycle DNA replication (sustained) [chronic cellular senescence] ∩ has part.negative regulation of telomere fusion [chronic cellular senescence] ∩ has part.negative regulation of tissue regeneration [chronic cellular senescence] ∩ has part.negative regulation of transcription by RNA polymerase II E2F (sustained) [chronic cellular senescence] ∩ has part.NfkB signaling [chronic cellular senescence] ∩ has part.oncogene activation [chronic cellular senescence] ∩ has part.organ malfunction [chronic cellular senescence] ∩ has part.p16 signaling (sustained) [chronic cellular senescence] ∩ has part.p21 signaling (sustained) [chronic cellular senescence] ∩ has part.p38 signaling [chronic cellular senescence] ∩ has part.p53 signaling [chronic cellular senescence] ∩ has part.paracrine signaling [chronic cellular senescence] ∩ has part.phospholipid peroxidation in mitochondrial membrane [chronic cellular senescence] ∩ has part.PI3K signaling (sustained) [chronic cellular senescence] ∩ has part.positive regulation of apoptotic process [chronic cellular senescence] ∩ has part.positive regulation of autophagy [chronic cellular senescence] ∩ has part.positive regulation of carcinogenesis [chronic cellular senescence] ∩ has part.positive regulation of cell proliferation [chronic cellular senescence] ∩ has part.positive regulation of cellular senescence in neighboring cell [chronic cellular senescence] ∩ has part.positive regulation of inflammatory response [chronic cellular senescence] ∩ has part.positive regulation of innate immune response [chronic cellular senescence] ∩ has part.positive regulation of NfkB signaling [chronic cellular senescence] ∩ has part.positive regulation of reactive oxygen species biosynthetic process [chronic cellular senescence] ∩ has part.positive regulation of senescence-associated heterochromatin focus formation [chronic cellular senescence] ∩ has part.positive regulation of senescence-associated secretory phenotype (SASP) secretion [chronic cellular senescence] ∩ has part.positive regulation of tumor cell proliferation [chronic cellular senescence] ∩ has part.protein production associated with SASP [chronic cellular senescence] ∩ has part.RB activation (sustained) [chronic cellular senescence] ∩ has part.reactive oxygen species biosynthetic process (sustained) [chronic cellular senescence] ∩ has part.regulation of cell cycle [chronic cellular senescence] ∩ has part.regulation of gene expression by p53 [chronic cellular senescence] ∩ has part.release of cytosolic chromatin fragments (CCFs) [chronic cellular senescence] ∩ has part.response to metabolic stress [chronic cellular senescence] ∩ has part.response to oxidative stress (sustained) [chronic cellular senescence] ∩ has part.response to tumor cell proliferation [chronic cellular senescence] ∩ has part.SA-β-GAL acculumation [chronic cellular senescence] ∩ has part.SASP related protein expression by NF-kappa B [chronic cellular senescence] ∩ has part.senescence cell immune clearance (low) [chronic cellular senescence] ∩ has part.senescence-associated heterochromatin focus formation [chronic cellular senescence] ∩ has part.senescence-associated secretory phenotype (SASP) secretion [chronic cellular senescence] ∩ has part.STING signaling [chronic cellular senescence] ∩ has part.telomere shortening [chronic cellular senescence] ∩ has part.tissue malfunction [chronic cellular senescence] ∩ has part.tumor cell proliferation [chronic cellular senescence] ∩ has part.type I interferon production [chronic cellular senescence]) 1. Find the direct sub-processes of HOIP_0060337 DNA damage response signaling [adult cellular senescence] PREFIX rdfs: <http://www.